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NM_000512.5(GALNS):c.29G>A (p.Trp10Ter) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Feb 1, 2021
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001543344.7

Allele description [Variation Report for NM_000512.5(GALNS):c.29G>A (p.Trp10Ter)]

NM_000512.5(GALNS):c.29G>A (p.Trp10Ter)

Genes:
LOC130059762:ATAC-STARR-seq lymphoblastoid silent region 7883 [Gene]
GALNS:galactosamine (N-acetyl)-6-sulfatase [Gene - OMIM - HGNC]
TRAPPC2L:trafficking protein particle complex subunit 2L [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_000512.5(GALNS):c.29G>A (p.Trp10Ter)
HGVS:
  • NC_000016.10:g.88856849C>T
  • NG_008667.1:g.5118G>A
  • NM_000512.5:c.29G>AMANE SELECT
  • NM_001323543.2:c.-403G>A
  • NM_001323544.2:c.-124G>A
  • NP_000503.1:p.Trp10Ter
  • NC_000016.9:g.88923257C>T
Protein change:
W10*
Links:
dbSNP: rs1967945316
NCBI 1000 Genomes Browser:
rs1967945316
Molecular consequence:
  • NM_001323543.2:c.-403G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001323544.2:c.-124G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000512.5:c.29G>A - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Mucopolysaccharidosis, MPS-IV-A (MPS4A)
Synonyms:
MPS IVA; Morquio syndrome A; MPS 4A; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009659; MedGen: C0086651; Orphanet: 309297; Orphanet: 582; OMIM: 253000

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001547570Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 1, 2021)
germlineresearch

PubMed (7)
[See all records that cite these PMIDs]

SCV001761893GeneReviews
no classification provided
not providedgermlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV003914820Lifecell International Pvt. Ltd
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenicgermlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
Asiangermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Mucopolysaccharidosis IVA (Morquio A): identification of novel common mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene in Italian patients.

Tomatsu S, Filocamo M, Orii KO, Sly WS, Gutierrez MA, Nishioka T, Serrato OP, Di Natale P, Montaño AM, Yamaguchi S, Kondo N, Orii T, Noguchi A.

Hum Mutat. 2004 Aug;24(2):187-8.

PubMed [citation]
PMID:
15241807

Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels.

Dũng VC, Tomatsu S, Montaño AM, Gottesman G, Bober MB, Mackenzie W, Maeda M, Mitchell GA, Suzuki Y, Orii T.

Mol Genet Metab. 2013 Sep-Oct;110(1-2):129-38. doi: 10.1016/j.ymgme.2013.06.008. Epub 2013 Jun 26.

PubMed [citation]
PMID:
23876334
PMCID:
PMC3779837
See all PubMed Citations (8)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547570.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (7)

Description

Nonsense variant (PVS1_very strong); in vitro and vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; RNA studies evidenced exon skipping; no mutant protein detected by Western Blot analysis; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV001761893.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Lifecell International Pvt. Ltd, SCV003914820.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Asian1not providednot providedclinical testing PubMed (2)

Description

A Heterozygous Nonsense variant c.29G>A in Exon 1 of the GALNS gene that results in the amino acid substitution p.Trp10* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 1048248]. The observed variant has been previously reported in patients affected with mucopolysaccharidosis IVA (Zanetti, Alessandra et al., 2021). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Dec 24, 2023